2-[di-(lower alkyl) aminoethylthio]-4-lower alkyl-thiazole-5-carboxylic acid lower alkyl esters



nit States 2 [DI (LOWER ALKYL) AMINOETHYLTHIO1-4- LOWER ALKYL THIAZDLE 5CARBOXYLIC ACID LOWER ALKYL ESI'ERS Marion W. Harman and John J. DAmico,Nitro, W. Va., assignors to Monsanto Chemical Company, St. Louis, Mo., acorporation of Delaware N Drawing. Original application Mar. 29, 1956,Ser. No. 574,612, now Patent No. 2,900,299, dated Aug. 18, 1959. Dividedand this application Aug. 11, 1958, Ser. No. 758,639

2 Claims. (Cl. 260-302) l SM wherein M represents an aminoethyl groupand A and Y are selected from a group consisting of hydrogen, loweralkyl and carbonyl radicals. Carbonyl radicals are characterized by thepresence of a (3:0 linkage, such radicals comprising, by way of example,acetyl, benzoyl, carbomethoxy, carbethoxy and amido radicals.

The compounds may be prepared by reacting the mercaptothiazole,conveniently in aqueous alkaline solution, with a 2-chloroethylamine.Suitable mercaptothiazoles have, for the most part, been described inthe literature and include Z-mercapto 4-ethylthiazole, Z-mercapto4,5-dimethylthiazole, 2-mercapto 4-methylthiazole, Z-mercapto4,5-diethylthiazole and Z-mercapto 4-methyl S-thiazolecarboxylate.

The method of preparation and the application of the products asfungicides, as exemplified by control and destruction of wheat rust,will be understood from the following description and examples of theinvention. Since the production procedure is of wide application, it isto be understood that many analogous products to those specificallydescribed are capable of production and are within the scope of theclaims.

Example 1 Typical of the procedure followed for the production of thenew class of chemicals is the following procedure whereby 2 (2dimethylaminoethylthio)-4-methyl-5-thiazolylmethyl ketone, of thefollowing structure, is produ ced:

onscl c'iooom Into an agitated mixture of 86.6 parts (0.5 mole) of 2-mercapto-4-methyl-S-thiazolyl methyl ketone, 500 parts of water and 80parts (0.5 mole) of 25% caustic soda solution there was added a mixtureof 72 parts 0.5 mole) of 2-chloro-N,N-dimethylethylamine hydrochlorideand 80 parts (0.5 mole) of 25% caustic soda. The stirred reactionmixture was then heated at 50-60 C. for about 5 hours and thereafter wasallowed to cool to about 25 atent ice A C. The cooled reaction mixturewas then extracted with about 500 parts of diethyl ether and the etherextract washed with several successive portions of water or until thewash waters were neutral in reaction. The oily product was then driedover a suitable agent such as anhydrous sodium sulfate, and the residualether removed by vacuum drying or distillation under 1-2 mm. pressureand not above -90 C. An amber colored oil resulted, which on analysiswas found to contain 11.37% nitrogen. Theory nitrogen content for aproduct of the formula C H N OS is 11.46%. The product is insoluble inwater and heptane, is soluble in ether, acetone and chloroform and inhot benzene, ethyl acetate and ethyl alcohol.

Example 2 Following the procedure as described in Example 1, butreacting a charge comprising 328 parts (0.25- mole) of4-methyl-2-mercaptothiazole in 500 parts of water containing 40 parts(0.25 mole) of 25% caustic sodasolution treated with 36 parts (0.25mole) of 2-chloro-N,N- dimethylethylamine in 40 parts (0.25 mole) of 25%caustic soda solution, there again was produced an amber oil which onanalysis gave 13.73% nitrogen as compared to 13.85% calculated for C H NS The 4-rnethyl-2- (Z-dimethylaminoethylthio) thiazole has the structureand exhibited the same solubility characteristics as did the product ofExample 1.

Example 3 As another example of the new class of chemicals, ethyl4-methyl-2-(Z-dirnethylaminoethylthio) 5 thiazole carboxylate wasobtained by reacting a mixture of 50.3 parts (0.25 mole) of ethyl2-mercapto-4-methyl-5-thiazole carboxylate contained in 225 parts byweight of ethyl alcohol and 32.2 parts of 87% caustic potash with 36parts (0.25 mole) of 2-chloro-N,N-dimethylethylarnine hydrochloride. Themixture of the reactants shown was stirred and maintained at 2530 C. forabout 24 hours and was then filtered to remove the salt present. Excessalcohol was thereupon removed by evaporation in vacuo. The residue wasthen dissolved in 600 parts of chloroform and the chloroform solutionwas washed with water until the washings were neutral to litmus. Theproduct was then dried by suitable means, such as anhydrous sodiumsulfate, and the chloroform removed by distillation under vacuum. Theproduct is an amber oil, exhibiting the same solvent characteristics asthe product of Example 1, and on analysis was found to contain 23.85%sulfur. Theory sulfur content of a product of the formula As anotherexample of the invention, 4-methyl-2-(2- dimethylaminoethylthiwS-thiazolecarboxamide hydrate of the structure C S CHzCHaN: CH3); wasobtained by reacting a mixture of 69.6 parts (0.4

and then heated at 70-80 C. for about 2hours.

mole) of 2-mercapto-4-methyl-S-thiazole carboxamide in 500 parts ofwater and 57.6 parts (0.4 mole) of 2-chlor0- N,N-dimethylethylaminehydrochloride in 64 parts (0.4 mole) of 25% caustic soda solution. Theentire mixture as shown was stirred while maintaining at a temperatureof 25-30" C. for about 24 hours and then was cooled while stirring to atemperature of 5 C. and maintained thereat for about 2 hours. wasfiltered and washed with several small portions of cold water, was thenair dried and after recrystallization from water was found to melt at114-1 15 C. The tan colored crystals were soluble in hot waterandalcohol but insoluble in ether, acetone, chloroform and acetone. Onanalysis the product was found to contain 15.31% nitrogen and 23.72%sulfur as compared to 15.96% nitrogen and 24.34% sulfur calculated for CH N O S H O.

This compound inhibited Aspergz'llus niger at a dilution of 1:1,000 butwas not a rust eradicant.

Example 5 As still another example of the invention, 4-methyl-2-'(2'dimethylaminoethylthio) S-thiazolecarboxanilide was prepared. Thisproduct of the structure CHaC=C C ONHCsH N\ A .HzO CH2CHzN(CHz)2 wasobtained by reacting 100 parts (0.4 mole) ofZ-mercapto-4-methyl-5-thiazolecarboxanilide in 400 parts of water and 64parts (0.4 mole) of 25% caustic soda solution with 57.6 parts (0.4 mole)of 2-chloro-N,N-dimethylethylamine hydrochloride and 64 parts (0.4 mole)of 25% caustic soda solution. The mixture of the above-named reactantswere stirred for about 24 hours while maintain ng a temperature of 25-30C. Thereupon the mixture was cooled slightly and extracted with about700750 parts of chloroform, the chloroform solution was washed withwater until the water washings were neutral to litmus, whereupon thesolution was dried over an anhydrous medium such as anhydrous sodiumsulfate. After the drying step the chloroform was removed by vacuumdistillation and a tan solid melting at 92-94 C. was obtained. Theproduct was soluble in chloroform and ethyl alcohol, in hot ethylacetate and hot acetone but insoluble in water, ether, benzene andheptane. On analysis the product was found to contain 12.43% nitrogenand 18.89% sulfur as compared to 12.38% nitrogen and 18.89% sulfurcalculated for C H N OS H O.

Example 6 As another example of the invention, ethyl2-(2-dimethylaminoethylthio)-4-thiazole carboxylate, of the structure ofthe ethyl ester of bromoacetyl glyoxylic acid in a single 1 portion to asolution of 27.6 parts (0.25 mole) of ammonium dithiocarbamate in 150parts of ethyl alcohol. A sharp temperature rise of about 40 ensued. Themixture was stirred at room temperature for about 24 hours After coolingto about C., 300 parts of water was added and the product filtered, thesolid washed with cold water and air dried. The crystals afterpurification from alcohol melted at 131-132 C. By analysis of thecrystals there was found 7.38% nitrogen and 33.98% sulfur as com- Theprecipitate that resulted pared with 7.40% nitrogen and 33.88% sulfurcalculated for CGHIINOZSQ.

To 47.3 parts of the ethyl 2-mercapto-4-thiazole carboxylate so preparedin 400 ml. acetone was added 16.1 parts (0.25 mole) of 87% potassiumhydroxide solution, 36 parts (0.25 mole) of2-chloro-N,N-dimethylethylamine hydrochloride and 40 parts (0.25 mole)of 25 sodium hydroxide solution. After stirring at room temperature for24 hours and filtering, the acetone was removed in vacuo and a viscousoily product was obtained soluble in acetone, chloroform and benzene butinsoluble in water and ether. Analysis gave 10.78% nitrogen and 24.34%sulfur as compared with 10.76% nitrogen and 24.63% sulfur calculated forC H N O S Typical of the effectiveness of the products of the presentinvention as fungicides is the action of the new materials in protectingagainst the destructive action of the organism Puccinia rubigo-veratritici. in demonstrating this elfectiveness a rust susceptible varietyof wheat (Seneca) is planted in small clay pots filled with soil. Aboutten seeds are normally planted in each pot so to insure availability offive uniform plants for the test. The pots are held in a greenhouse atF. and watered daily until the seedlings were six days old. Thereuponthe seedlings were sprayed with water by means of an atomizer and bloom"removed from the leaves by gentle rubbing. Then rust spores weretransferred to the leaves and rubbed up and down the leaves. Four daysafter inoculation with rust spores, the plants were sprayed withsolutions of the chemical under test, prepared in concentrations of from1 to 5 parts chemical to 1000 parts of Water which may contain a smallquantity (5 parts) of acetone if the chemical is not water soluble. Atrace of a suitable spreading or wetting agent preferably is alsopresent.

The plants are sprayed in duplicate tests using 10 cc. of

the test solution per pot. After treatment as described, the pots areheld in the greenhouse for a week and examined and graded as to thenumber and size of pustules formed on the leaves. The products ofExamples 2 and 3 hereinbefore described, taken as typical of theproducts herein disclosed, in concentrations between 1 to 5 parts per1000, that is of from 0.1 to 0.5% by weight, showed good results asfoliage eradicants of wheat rust. There was also from no to very slightinjury of the leaves so the products are not phytotoxic as well as beinggood fungicides.

It is intended to cover all changes and modifications of the examples ofthe invention herein chosen for purposes of disclosure which do notconstitute departures from the spirit and scope of the invention.

This application is a division of application Serial No. 574,6l2. nowPatent No. 2,900,299.

What is claimed is:

1. A compound of the structure References Cited in the file of thispatent UNITED STATES PATENTS Mathes et a1 July 15, 1947 DAmico Oct. 25,1955 OTHER REFERENCES Creed et al., Ind. Eng. Chem., vol. 46, pp.808-816 (1954).

1. A COMPOUND OF THE STRUCTURE